ABSTRACT The pandemic prompted by the novel SARS-COV-2 virus continues to have a devastating impact on the health of communities, clinically, socially and economically. Preventive approaches require an understanding of the virus prevalence and herd immunity in the general population. To evaluate the sero-prevalence of immunity against SARS-COV-2 in the United States, this scientific partnership of academic medical centers and the NIH's intramural research program will examine the population prevalences of detectable antibodies to SARS- COV-2 from a convenience sampling of adults in the U.S. who have not been diagnosed with COVID-19 (Aim 1) and will determine the immune attributes associated with health outcomes (Aim 2), including for those in underrepresented populations and across the life course. From a cohort of >400,000 self-referred, asymptomatic adults nationwide, a near-representative subset will be selected based on demographics such as age, race/ethnicity, and geography to provide blood samples for characterization of antibodies and other immunologic markers to inform the development of screening and neutralization assays. This work benefits from the deep expertise in the basic and applied research of infectious diseases as well as viral vaccine development, host immune response to viruses, and viral molecular biology and genetics at the National Institute for Allergy and Infectious Diseases (NIAID). It also leverages the rigorous and efficient capacity maintained by Clinical and Translational Science Awards (CTSA) Hubs to rapidly engage diverse cohorts of participants nationally to accelerate translational research that is high priority scientifically and for eventual public health practice. From this study, the collaborative team will gain crucial insights into the magnitude of the COVID-19 pandemic across the country and will identify potential targets for a vaccine. These data are essential to assess the impact of public health efforts and to guide ongoing COVID-19 response.